Sanguinarine ameliorates rheumatoid arthritis by activating the Hippo-YAP/TAZ pathway to induce apoptosis and suppress inflammation in fibroblast-like synoviocytes.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disease with progressive joint damage, functional disability and systemic comorbidity. Available therapies are not satisfactory, including low rates of remission and about 30% of patients with poor response to first-line treatment. Thus, more effective therapeutic strategies are urgently needed. Sanguinarine, a benzophenanthridine alkaloid primarily isolated from Sanguinaria canadensis and other members of the Papaveraceae family, has been documented to possess notable anti-bacterial, anti-inflammatory, and anti-neoplastic properties. Nevertheless, its potential utility as a targeted therapeutic modality for RA has yet to be systematically investigated.

METHODS: Here, we demonstrate that sanguinarine can effectively ameliorate the development of adjuvant-induced arthritis in rats and decrease arthritis scores, attenuate the inflammatory response, and prevent bone and joint damage.

RESULTS: Flow cytometry and ELISA both confirmed its anti-inflammatory activity, reducing the levels of PGE2, TNF-α, IL-1, and IL-6. In human fibroblast-like synoviocytes from RA patients (HFLS-RA), sanguinarine triggered cell apoptosis accompanied by elevated intracellular ROS, loss of mitochondrial membrane potential and activation of caspase-3, and activated the Hippo/YAP pathway both in vitro and in vivo.

DISCUSSION: These results suggest that sanguinarine ameliorates RA by activation of the Hippo-YAP/TAZ pathway to induce apoptosis and suppress inflammation, highlighting its potential as a novel therapeutic candidate for RA.